The earliest drug delivery systems, first introduced in the 1970s, were based on polymers formed from lactic and glycolic acids. Today, polymeric materials still provide the most important avenues for research, primarily because they are easy to process and researchers can readily control their chemical and physical properties via molecular synthesis. Basically, two broad categories of polymer systems, both known as “microspheres” because of their size and shape, have been studied: reservoir systems and matrix systems. The former involves the encapsulation of a pharmaceutical product within a polymer shell; whereas the latter describes a system in which a drug is physically entrapped or matrixed within a polymer network.
The release of medications from either category of polymer system traditionally has been diffusion-controlled. Currently, however, modern research is aimed at investigating biodegradable polymer systems. These drug deliverers, for example polyhydoxyalkanoates, degrade into biologically acceptable compounds, often through the process of hydrolysis, and leave their incorporated medications behind. This erosion process occurs either in bulk (wherein the matrix degrades uniformly) or at the polymer's surface (whereby release rates are related to the polymer's surface area). The degradation process itself involves the breakdown of these polymers into lactic and glycolic acids. These acids are eventually reduced by the Kreb's cycle to carbon dioxide and water, which the body can easily expel.
Amino Acid based Bioanalogous Biopolymers (AABB)—a new family of hydrophobic α-amino acid based polymers—recently has been developed. Poly(ester amides), (PEAs) and poly(ester urethanes) (PEURs) with linear structures, which are based on essential α-amino acids, fatty dicarboxylic acids and aliphatic diols have been synthesized via an Active Polycondensation (APC) method. The APC method mainly is conducted in solution under mild temperatures without use of any toxic catalyst. Using this method, a large variety of AABB polymers with a broad range of physical and thermo-mechanical properties and biodegradation profiles have been reported and studied. See review paper and references therein by R. Katsarava (Macromol. Symp. (2003) 199:419-429).
In particular, amino acid-based poly(ester amide) (PEA) and poly(ester urethane) (PEUR) polymers demonstrate enzyme-mediated surface degradation (G. Tsitlanadze, et al. J. Biomater. Sci. Polym. Edn. (2004) 15:1-24) and a low inflammation profile (K. DeFife et al. Transcatheter Cardiovascular Therapeutics—TCT 2004 Conference. Poster presentation. Washington D.C. (2004)). These properties make PEAs and PEURs excellent materials for a variety of different medical and pharmaceutical applications.
Another significant advantage of the APC method is that PEAs and PEURs with programmed physical and mechanical properties as well as biodegradable profiles can be achieved simply by varying three components in the building blocks during their synthesis: naturally occurring amino acids and, therefore, hydrophobic α-amino acids, non-toxic fatty diols and aliphatic dicarboxylic acids. From these components, the following building blocks are built and subjected to the APC method: nucleophilic monomers of bis-(α-amino acid)-α,ω-alkylene diesters and bis-electrophiles, which are activated esters of di-acids, for example, bis-(p-nitrophenyl) diesters of fatty di-acids.
Recently, a series of new unsaturated biodegradable PEAs also have been reported, wherein two different types of unsaturation can be introduced into the main backbone: naturally occurring fumaric acid as a di-acid component or 2-butene-1,4-diol-diester as an unsaturated diol partner (K. Guo, et al. Synthesis and Characterization of Novel Biodegradable Unsaturated Poly(ester-amides). J. Polym. Sci: Part A: Polym. Chem. (2005) 43:1463-1477). These unsaturated PEAs, particularly polymers based on fumaric acid, showed poor solubility in most organic solvents, high glass transition temperatures in the range of 96° C.-109° C., and sharp melting endotherms in the range of 220° C.-250° C., a thermal profile of that also can be interpreted as indicating simultaneous thermal crosslinking of the polymers.
The physical properties of PEAs and PEURs are heavily dependent on the structure of the polymer backbone, as shown in recent works (Katsarava R, et al. J. Polym. Sci: Part A: Polymer Chemistry, 37, 391-407 (1999) and U.S. Pat. No. 6,503,538 B1). For example, replacement of aliphatic diols in the backbone with bicyclic rigid fragments of “sugar-diols”—1,4:3,6-dianhydrohexytols has been shown to significantly increase the glass transition temperature (Tg) of PEAs, providing a glass transition temperature as high as 103° C., while esterase-mediated degradation rates remained in the same order of magnitude as those for other PEAs and PEURs (Z. Gomurashvili, et al. J. Macromol. Sci. Pure Appl. Chem. (2000) A37:215-227 and M. Okada et al. J. Appl. Polym. Sci. (2001) 81:2721-2734). However, the sugar-diol containing PEAs of this study tend to be unduly rigid.
Thus, there is a need in the art for more and better varieties of biocompatible polymer compositions and methods for delivering therapeutic molecules, such as drugs and other bioactive agents, at a controlled rate of therapeutic or palliative release, while affording enhanced mechanical and physical properties.